rs397508096
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.153C>A(p.Tyr51*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ1
NM_000218.3 stop_gained
NM_000218.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: -0.203
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-2445251-C-A is Pathogenic according to our data. Variant chr11-2445251-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 933168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.153C>A | p.Tyr51* | stop_gained | 1/16 | ENST00000155840.12 | NP_000209.2 | |
KCNQ1 | NM_001406836.1 | c.153C>A | p.Tyr51* | stop_gained | 1/15 | NP_001393765.1 | ||
KCNQ1 | NM_001406838.1 | c.153C>A | p.Tyr51* | stop_gained | 1/11 | NP_001393767.1 | ||
KCNQ1 | NM_001406837.1 | c.-210C>A | 5_prime_UTR_variant | 1/17 | NP_001393766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.153C>A | p.Tyr51* | stop_gained | 1/16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000646564.2 | c.153C>A | p.Tyr51* | stop_gained | 1/11 | ENSP00000495806.2 | ||||
KCNQ1 | ENST00000496887.7 | c.24-132C>A | intron_variant | 5 | ENSP00000434560.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1046344Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 500542
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1046344
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30
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0
AN XY:
500542
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2020 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This nonsense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 30758498, 15840476). ClinVar contains an entry for this variant (Variation ID: 933168). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Tyr51*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). - |
Cardiac arrhythmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2020 | Variant summary: KCNQ1 c.153C>A (p.Tyr51X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 34442 control chromosomes (gnomAD). c.153C>A has been reported in the literature in an individual affected with congenital LQTS (Shimizu_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, a different variant resulting in the same codon effect (c.153C>G, p.Tyr51X) is reported in ClinVar and other online databases (e.g. HGMD, LOVD, The Gene Connection for the Heart) as pathogenic and as disease-associated. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at